For several decades, the use of the Eschweiler-Clarke ("E-C" for brevity) reaction has been used in laboratory procedures for the methylation of simple acyclic and cyclic amines, with excellent results, the reaction proceeding essentially quantitatively with only a relatively small excess of formaldehyde (HCHO) and enough formic acid (HCOOH) to solvate the amine reactant, typically from a 2-fold to 4-fold molar excess of HCOOH. If a much larger excess of HCHO and HCOOH is necessary, the E-C reaction is not used, as far as we know, commercially. The reason is that it is impractical to recover the unused excess reactants.
Because of the convenient and economical way in which the E-C reaction can introduce a methyl substituent on an amine N atom, the reaction has attracted particular attention for the methylation of the hindered N atom of hindered piperidyl, piperazinyl, piperazin-2-one, diazepine and diazepin-2-one groups, in stabilizer compounds commonly referred to as "hindered amines". Except that, because of the highly hindered N atom to be methylated, the reaction is usually carried out in the laboratory with at least a 2-fold molar excess of HCHO and a much larger excess of HCOOH. Most of the excess HCOOH is recoverable for reuse by an economical distillation but excess of HCHO is wasted. Thus, with a 2-fold molar excess of HCHO, one mole is wasted for each mole used. This is too large an excess of HCHO to be economical. I decided to investigate solutions to this problem, namely the methylation of the hindered N atom in hindered amine light and heat stabilizers for organic compounds.
In UK Pat. appl. GB 2,194,237 (Mar. 2, '88) piperidyl-containing compounds were methylated using the E-C procedure. Example 1 discloses preparation of a tetramine containing plural triazine rings, each substituted with two pentamethylated piperidyl substituents. The amine to be methylated is N.sup.1,N.sup.2,N.sup.3, N.sup.4 -tetrakis-[2,4-bis[N-(2,2,6,6-tetramethyl-4-piperidyl)-n-butylamino]-l,1,3 ,5-triazin-6-yl]-4,7-diazadecane-1,10-diamine; it has 2 terminal -NH groups and 8 tetramethyl-4-piperidyl substituents, each with a &gt;NH group. To a solution of 0.02 moles of this amine in 100 ml of water is added 0.4 moles of formic acid (two-fold molar excess) and 0.4 moles of a 40% aqueous formaldehyde solution (two-fold molar excess). The solution is heated under reflux for 8 hr; after cooling to room temperature, an additional amount of 0.2 moles (stoichiometric for all NH groups to be methylated) of 40% formaldehyde is added and the solution refluxed for an additional 5 hr. Repeating this reaction with a simpler piperidyl-substituted compound and a two-fold excess of HCHO and HCOOH, I found that methylation proceeded with excellent conversion, albeit relatively slowly. However, when the reaction was starved of HCHO by decreasing the molar excess of HCHO to 50% (in steps, from 200%) the reaction mass was so difficult to work up, that a NMR (nuclear magnetic resonance) mass spectrographic analysis of the concentrated reaction mass had to done, and this indicated less than 50% methylation of the &gt;NH group irrespective of how much HCOOH was used.
Several methylated piperazine- and piperazin-2-one-containing stabilizers have been disclosed in Japanese Pat. application No. 63-86711 published Apr. 18 1988. In such PSP-containing compounds, the hindered N.sup.4 atom in the diazacycloalkan-2-one ring is substituted at both the 3-and 5- positions. The N.sup.4 atom is hindered in all such PSPs. This N.sup.4 atom is termed "the hindered N atom" because it is flanked by disubstituted 3- and 5-carbon atoms, either or both of which may have a spiro substituent. Homologous (with the piperazin-2-ones) are diazepin-2-one compounds containing a seven-membered diaza ring. The polysubstituted piperazin-2-one ("PSP") and diazepin-2-one substituents are each diazacycloalkan-2-one substituents which are together referred to herein by the acronym "DCA", for convenience.
A polysubstituted diazacycloalkan-2-one and compounds containing one or more DCA substituents are "DCA-containing" compounds referred to herein as "complex amines". In the Japanese reference, methylated PSP stabilizers are said to improve the color of polyacetals. There is no teaching of how such methylated compounds were prepared, but because such methylated stabilizers are not commercially available, it is expected they were synthesized in the laboratory. Since I was particularly interested in methylating DCA-containing compounds, and more particularly, PSP-containing compounds, my efforts were directed to converting an uneconomical laboratory process for methylating such compounds to an economical one.
The process of this invention exploits the peculiar and unique susceptibility of a DCA group to a starved E-C procedure. The unique configuration of a DCA group imbues it with characteristics which permit easy methylation of only the NH groups in the DCA, while failing to methylate other -NH groups which may be present in complex amines.
Examples of DCAs are those referred to in U.S. Pat. No. 4,190,571 the disclosure of which is incorporated by reference thereto as if fully set forth herein, and the aforementioned Japanese 63-86711. Illustrative of DCA-containing compounds are (a) triazine compounds having PSP substituents such as those disclosed in U.S. Pat. Nos. 4,480,092; 4,629,752; and, 4,639,479 (referred to as "PIP-T" compounds); and (b) N-(substituted)-.alpha.-(3,5-dialky-4-hydroxyphenyl)-.alpha.,.alpha.-disub stituted acetamides disclosed in U.S. Pat. No. 4,780,495 (referred to as "3,5-DHPZNA" compounds); the disclosure of each of which foregoing references is incorporated by reference thereto as if fully set forth herein. Methylated PSPs, 3,5-DHPZNAs and PIP-Ts, in each of which the NH groups are methylated, are excellent stabilizers for polyoxymethylene resins, particularly polyacetals.
A typical E-C process is described under the heading "Methylation of Amines with Formaldehyde" in Organic Reactions, Vol V by M. L. Moore, pg 307 et seq., as follows: "One molecular proportion (or slight excess) of formaldehyde and two to four molecular proportions of formic acid are used for each methyl group introduced, indicating that it is mainly the formic acid that supplies the hydrogen involved in the reduction. The reaction is carried out on a steam bath." The HCHO contributes the carbon atom of the methyl group, the HCOOH solvates the amine reactant and provides the hydrogen (proton) for reduction.
This typical E-C reaction, carried out with a primary or secondary amine, results in the methylated amine when the reactants are heated for several hours after the evolution of gas has ceased. The formic acid functions as both a co-reactant and a solvent. The function of formic acid as a solvent is particularly important when the amine to be methylated is poorly soluble in water.
Unhindered amines such as benzylamine and secondary amines such as piperidine and piperazine are expected to be methylated with a slight excess of HCHO to give almost theoretical conversion to the corresponding methylated amines, and in practice, provides a highly acceptable conversion, even if not quantitative. But because hindered amines are so highly hindered, they are not expected to provide essentially complete conversion, are expected to require a large excess of HCHO. The overall yield of the reaction is further reduced by the difficulty of recovering the desired product from the reaction mass ("work-up"). The result is an unacceptably low yield from a high-priced complex amine starting material, and the low yield makes the E-C process uneconomical.
In a text-book procedure for a typical E-C reaction (see Moore, supra pg 323), benzylamine (1 mole) is added with cooling, to 5 moles of 90% formic acid. Then 2.2 moles of 35% formaldehyde solution is added, and the mixture is heated on a steam bath under reflux for 2 to 4 hours after evolution of gas has ceased (8 to 12 hr in all). Slightly more than 1 mole of concentrated hydrochloric acid is then added and the formic acid and any excess formaldehyde are evaporated on a steam bath. The colorless residue is dissolved in water and made alkaline by the addition of 25% aqueous sodium hydroxide, and distilled over sodium. The product, N,N-dimethylbenzylamine is recovered in excellent yield.
Carrying out this reaction commercially is burdened with the costs of recovering the large excess of formaldehyde or formic acid, or both. For example, Czech appln. No. 82/5562 filed July 21, 1982 discloses treating the methylated product with HCl, then distilling under vacuum to remove volatiles. The yield was 66-70% which is commercially unacceptable because of the high cost of a DCA-containing amine to be methylated. Such a distillation process still leaves the problem of separating the large excess of formic acid from the formaldehye.
Separating formaldehyde and formic acid as aqueous solutions of chosen concentration (which may later be diluted) by distillation, is not practical because of the too-close boiling points. For example, USSR appln No. 80/22299, filed Oct 10, 1980 discloses distillation in a column the pressure at the top and bottom of which was 20 mm and 2 atm respectively.
My process is applicable only to the methylation of DCA-containing compounds and not to piperidines or diazacycloalkanes because the latter two are not susceptible to methylation when starved of HCHO. It was surprising that only a DCA group can be methylated with only a bare excess of formaldehyde, much less than the amount one would typically expect to use in a conventional E-C reaction (hence my process is referred to as the "starved E-C process"). The amount of water present during the starved E-C reaction is not critical except for the effect on the time required to complete the reaction. In general, the more dilute the reaction mass, the longer the time for the reaction, and in a commercial process, it is generally desired to run under conditions which provide maximum reactor productivity.
Neither could it have been foreseen that, after the reaction is completed and the formic acid neutralized with sufficient aqueous alkali to make the reaction mass basic ("basified"), the methylated product would separate from solution, and would be so insoluble in water that it could be washed with water without sacrificing any more than 1% of its weight. This ability to wash out essentially all impurities from the solvent phase, including unreacted formaldehyde, formic acid and salt formed upon neutralization, enhances the efficiency of, and vastly simplifies the recovery procedure for the methylated product. It will be recognized that not all methylated complex amines will be so insoluble as to lose less than 5% upon repeated washing with water, so that my process is specifically directed to those which do.
Irrespective of the dilution of the reaction mass with water, the starved E-C reaction is carried out at above about 60.degree. C., and CO.sub.2 formed during the reaction is driven off. A higher temperature shortens the time for the reaction, producing the methylated DCA substantially quantitatively, typically in less than 8 hr.
It will be evident from the foregoing, that the steps under which adequate conversion is obtained in a reasonable amount of time, and the steps of a "work-up", taking advantage of the substantial insolubility of the methylated complex amine in water (under process conditions provided in the recovery system), must together provide a high enough yield of essentially pure product to make the process commercially successful.
The difficulty of methylating the hindered N atom of a piperidyl group, Piccinelli et al (Eur. Pat. appln. 0319480 published June 7, 1989) used an alkylbenzene solvent in a modification of the usual E-C procedure. They methylated triazine compounds containing 2,2,6,6-tetramethylpiperidyl groups. But there is no indication of either what percentage of the piperidyl groups were methylated, or what the yields might have been.
My process relates specifically to methylating the hindered N atom of a DCA group by starving the well-known E-C reaction of HCHO, yet achieving essentially stoichiometrically complete conversion of the &gt;NH group(s) in any DCA-containing compound. This process takes advantage of the discovery that the NH group in a DCA is uniquely susceptible to methylation without a large excess of HCHO. This discovery provides the basis for a commercial process.